Management of infusion-related reactions in cancer therapy: strategies and challenges.

Several anticancer therapies have the potential to cause infusion-related reactions (IRRs) in the form of adverse events that typically occur within minutes to hours after drug infusion. IRRs can range in severity from mild to severe anaphylaxis-like reactions. Careful monitoring at infusion initiation, prompt recognition, and appropriate clinical assessment of the IRR and its severity, followed by immediate management, are required to ensure patient safety and optimal outcomes. Lack of standardization in the prevention, management, and reporting of IRRs across cancer-treating institutions represents not only a quality and safety gap but also a disparity in cancer care. The present article, supported by recently published data, was developed to standardize these procedures across institutions and provide a useful tool for health care providers in clinical practice to recognize early signs and symptoms of an IRR and promptly and appropriately manage the event.

Unresectable stage III non-small cell lung cancer: Insights from a Portuguese expert panel.

INTRODUCTION: The management of unresectable stage III non-small cell lung cancer (NSCLC) is clinically challenging and there is no current consensus on optimal strategies. Herein, a panel of Portuguese experts aims to present practical recommendations for the global management of unresectable stage III NSCLC patients. METHODS: A group of Portuguese lung cancer experts debated aspects related to the diagnosis, staging and treatment of unresectable stage III NSCLC in light of current evidence. Recent breakthroughs in immunotherapy as part of a standard therapeutic approach were also discussed. This review exposes the major conclusions obtained. RESULTS: Practical recommendations for the management of unresectable stage III NSCLC were proposed, aiming to improve the pathways of diagnosis and treatment in the Portuguese healthcare system. Clinical heterogeneity of patients with stage III NSCLC hinders the development of single standardised algorithm where all fit. CONCLUSIONS: A timely diagnosis and a proper staging contribute to the best management of each patient, optimizing treatment tolerance and effectiveness. The expert panel considered chemoradiotherapy as the preferable approach when surgery is not possible. Management of adverse events and immunotherapy as a consolidation therapy are also essential steps for a successful strategy.

Lignin-enriched tricalcium phosphate/sodium alginate 3D scaffolds for application in bone tissue regeneration.

The bone is a connective, vascularized, and mineralized tissue that confers protection to organs, and participates in the support and locomotion of the human body, maintenance of homeostasis, as well as in hematopoiesis. However, throughout the lifetime, bone defects may arise due to traumas (mechanical fractures), diseases, and/or aging, which when too extensive compromise the ability of the bone to self-regenerate. To surpass such clinical situation, different therapeutic approaches have been pursued. Rapid prototyping techniques using composite materials (consisting of ceramics and polymers) have been used to produce customized 3D structures with osteoinductive and osteoconductive properties. In order to reinforce the mechanical and osteogenic properties of these 3D structures, herein, a new 3D scaffold was produced through the layer-by-layer deposition of a tricalcium phosphate (TCP), sodium alginate (SA), and lignin (LG) mixture using the Fab@Home 3D-Plotter. Three different TCP/LG/SA formulations, LG/SA ratio 1:3, 1:2, or 1:1, were produced and subsequently evaluated to determine their suitability for bone regeneration. The physicochemical assays demonstrated that the LG inclusion improved the mechanical resistance of the scaffolds, particularly in the 1:2 ratio, since a 15 % increase in the mechanical strength was observed. Moreover, all TCP/LG/SA formulations showed an enhanced wettability and maintained their capacity to promote the osteoblasts' adhesion and proliferation as well as their bioactivity (formation of hydroxyapatite crystals). Such results support the LG inclusion and application in the development of 3D scaffolds aimed for bone regeneration.

Apparent regional differences in the spectrum of BARD1 pathogenic variants in Spanish population and importance of copy number variants.

Only up to 25% of the cases in which there is a familial aggregation of breast and/or ovarian cancer are explained by germline mutations in the well-known BRCA1 and BRCA2 high-risk genes. Recently, the BRCA1-associated ring domain (BARD1), that partners BRCA1 in DNA repair, has been confirmed as a moderate-risk breast cancer susceptibility gene. Taking advantage of next-generation sequencing techniques, and with the purpose of defining the whole spectrum of possible pathogenic variants (PVs) in this gene, here we have performed a comprehensive mutational analysis of BARD1 in a cohort of 1946 Spanish patients who fulfilled criteria to be tested for germline pathogenic mutations in BRCA1 and BRCA2. We identified 22 different rare germline variants, being 5 of them clearly pathogenic or likely pathogenic large deletions, which account for 0.26% of the patients tested. Our results show that the prevalence and spectrum of mutations in the BARD1 gene might vary between different regions of Spain and expose the relevance to test for copy number variations.

Participatory visual arts activities for people with dementia: a review.

AIMS: To report and summarise the effects of interventions using participatory visual arts activities in dementia research through a narrative synthesis systematic review. METHODS: We searched four databases MEDLINE, EMBASE, PsycINFO and Applied Social Sciences Index & Abstracts (ASSIA). Of the 3263 records retrieved, 20 were included in this review. Quality was assessed with the Critical Appraisal Skills Programme (CASP) and the Downs and Black checklist. RESULTS: The use of participatory visual arts has positive effects on cognition, social and psychological functioning of people with dementia, although the diversity of the studies provided inconsistent evidence of an overall positive effect. Participants evaluated the interventions as enjoyable and engaging. CONCLUSIONS: This review adds to previous work done by Deshmukh et al. and Windle et al. with a focus on studies that had participatory visual art-making activities made by people with dementia. The use of participatory arts may bring benefits for people with dementia. The heterogeneity of the interventions prevented generalisation of the results. Criteria associated with positive outcomes of the intervention are reported to aid on the design of participatory visual arts interventions for people with dementia. Future research in participatory arts should have a more detailed description of the methods and art interventions.

AMP-activated protein kinase (AMPK) signaling in GnRH neurons links energy status and reproduction.

BACKGROUND: Reproduction is tightly coupled to body energy and metabolic status. GnRH neurons, master elements and final output pathway for the brain control of reproduction, directly or indirectly receive and integrate multiple metabolic cues to regulate reproductive function. Yet, the molecular underpinnings of such phenomenon remain largely unfolded. AMP-activated protein kinase (AMPK), the fundamental cellular sensor that becomes activated in conditions of energy deficit, has been recently shown to participate in the control of Kiss1 neurons, essential gatekeepers of the reproductive axis, by driving an inhibitory valence in situations of energy scarcity at puberty. However, the contribution of AMPK signaling specifically in GnRH neurons to the metabolic control of reproduction remains unknown. METHODS: Double immunohistochemistry (IHC) was applied to evaluate expression of active (phosphorylated) AMPK in GnRH neurons and a novel mouse line, named GAMKO, with conditional ablation of the AMPK α1 subunit in GnRH neurons, was generated. GAMKO mice of both sexes were subjected to reproductive characterization, with attention to puberty and gonadotropic responses to kisspeptin and metabolic stress. RESULTS: A vast majority (>95%) of GnRH neurons co-expressed pAMPK. Female (but not male) GAMKO mice displayed earlier puberty onset and exaggerated LH (as surrogate marker of GnRH) responses to kisspeptin-10 at the prepubertal age. In adulthood, GAMKO females retained increased LH responsiveness to kisspeptin and showed partial resilience to the inhibitory effects of conditions of negative energy balance on the gonadotropic axis. The modulatory role of AMPK in GnRH neurons required preserved ovarian function, since the differences in LH pulsatility detected between GAMKO and control mice subjected to fasting were abolished in ovariectomized animals. CONCLUSIONS: Altogether, our data document a sex-biased, physiological role of AMPK signaling in GnRH neurons, as molecular conduit of the inhibitory actions of conditions of energy deficit on the female reproductive axis.

Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC).

OBJECTIVE: The main aim of the study was to evaluate the efficacy and safety profile of Nivolumab, an immune-checkpoint-inhibitor antibody, in advanced, previously treated, Non-Small Cell Lung Cancer (NSCLC) patients, in a real world setting. METHODS: We performed a retrospective, multicentre data analysis of patients who were included in the Portuguese Nivolumab Expanded Access Program (EAP). Eligibility criteria included histologically or citologically confirmed NSCLC, stage IIIB and IV, evaluable disease, sufficient organ function and at least one prior line of chemotherapy. The endpoints included Overall Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Safety analysis was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and immune-related Adverse Events (irAEs) were treated according to protocol treatment guidelines. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Data was analysed using SPSS, version 21.0 (IBM Statistics). RESULTS: From June 2015 to December 2016, a total of 229 patients with advanced NSCLC were enrolled at 30 Portuguese centres. Clinical data were collected up to the end of July 2018. The baseline median age was 64 years (range 37-83) and the majority of patients were males (70.3%) and former/current smokers (69.4%). Patients with non-squamous histology predominated (88.1%), and 67.6% of the patients had received 2 or more prior lines of chemotherapy. Out of 229 patients, data was available for 219 patients (3 patients did not start treatment, while data was unavailable in 7 patients); of the 219 patients, 15.5% were not evaluated for radiological tumour assessment, 1.4% had complete response (CR), 21% partial response (PR), 31% stable disease (SD) and 31.1% progressive disease (PD). Thus, the ORR was 22.4% and DCR was 53.4% in this population. At the time of survival analysis the median PFS was 4.91 months (95% CI, 3.89-6.11) and median OS was 13.21 months (95% CI, 9.89-16.53). The safety profile was in line with clinical trial data. CONCLUSIONS: Efficacy and safety results observed in this retrospective analysis were consistent with observations reported in clinical trials and from other centres.

Small for gestational age very preterm infants present a higher risk of developing bronchopulmonary dysplasia.

INTRODUCTION: Several studies assessed the influence of a low birth weight on bronchopulmonary dysplasia (BPD), but not all could find a significant association. Our aim was to assess the association between low birth weight and BPD in preterm infants, prospectively recruited at 11 level III Portuguese neonatal centers. METHODS: Obstetrical and neonatal data on mothers and preterm infants with gestational ages between 24 and 30 weeks, born during 2015 and 2016 after a surveilled pregnancy, were analyzed. Neonates were considered small for gestational age (SGA) when their birthweight was below the 10th centile of Fenton's growth chats and BPD was defined as the dependency for oxygen therapy until 36 weeks of corrected age. Statistical analysis was performed using IBM SPSS® statistics 23 and a p-value <0.05 was considered statistically significant. RESULTS: Out of 614, a total of 494 preterm infants delivered from 410 women were enrolled in the study; 40 (8.0%) infants with SGA criteria. SGA were more often associated with a single pregnancy, had greater use of antenatal corticosteroids, increased prevalence of gestational hypertensive disorders, C-section, rupture of membranes below 18 hours, rate of intubation in the delivery room, use of surfactant treatment, oxygen therapy, mechanical ventilation need, BPD, cystic periventricular leukomalacia, nosocomial sepsis and pneumonia; had lower prevalence of chorioamnionitis, and lower Apgar scores. The multivariate analysis by logistic regression, adjusted for BPD risk factors revealed a significant association between SGA and BPD: OR = 5.2 [CI: 1.46-18.58]; p = 0.01. CONCLUSION: The results of this study increase the scientific evidence that SGA is an independent risk factor for BPD.

EUS-guided tissue acquisition in the study of the adrenal glands: Results of a nationwide multicenter study.

BACKGROUND: There are limited data about the role of endoscopic ultrasound-guided tissue acquisition (EUS-TA), by fine needle aspiration (EUS-FNA) or biopsy (EUS-FNB), in the evaluation of the adrenal glands (AG). The primary aim was to assess the diagnostic yield and safety. The secondary aims were the malignancy predictors, and to create a predictive model of malignancy. METHODS: This was a retrospective nationwide study involving all Spanish hospitals experienced in EUS-TA of AGs. Inclusion period was from April-2003 to April-2016. Inclusion criteria: all consecutive cases that underwent EUS-TA of AGs. EUS and cytopathology findings were evaluated. Statistical analyses: diagnostic accuracy of echoendoscopist's suspicion using cytology by EUS-TA, as gold standard; multivariate logistic regression model to predict tumor malignancy. RESULTS: A total of 204 EUS-TA of AGs were evaluated. Primary tumor locations were lung70%, others19%, and unknown11%. AG samples were adequate for cytological diagnosis in 91%, and confirmed malignancy in 60%. Diagnostic accuracy of the endosonographer's suspicion was 68%. The most common technique was: a 22-G (65%) and cytological needle (75%) with suction-syringe (66%). No serious adverse events were described. The variables most associated with malignancy were size>30mm (OR2.27; 95%CI, 1.16-4.05), heterogeneous echo-pattern (OR2.11; 95%CI, 1.1-3.9), variegated AG shape (OR2.46; 95%CI, 1-6.24), and endosonographer suspicion (OR17.46; 95%CI, 6.2-58.5). The best variables for a predictive multivariate logistic model of malignancy were age, sex, echo-pattern, and AG-shape. CONCLUSIONS: EUS-TA of the AGs is a safe, minimally invasive procedure, allowing an excellent diagnostic yield. These results suggest the possibility of developing a pre-EUS procedure predictive malignancy model.

Elderly patients with advanced NSCLC: The value of geriatric evaluation and the feasibility of CGA alternatives in predicting chemotherapy toxicity.

Cancer is primarily a disease of the elderly, with the incidence of older patients with cancer expected to increase in the coming years. Despite remarkable advances during the last decade, lung cancer remains a leading cause of mortality worldwide, non-small cell lung cancer (NSCLC) being the dominant (85-90%) subtype. At diagnosis, 50% of NSCLC patients are ≥70 years and 15%, over 80 years of age. Due to their under-representation in clinical trials, current treatment decisions for older patients with cancer are based on a low level of scientific evidence. The little evidence that exists suggests that chemotherapy is effective in elderly NSCLC patients, but also indicates that they are at more risk of chemotherapy toxicity than younger adults. However, if carefully selected and monitored, elderly patients can benefit from standard chemotherapy regimens. The Comprehensive Geriatric Assessment (CGA) has historically been adopted to identify elderly patients who are unfit for chemotherapy, yet in clinical practice this is often not feasible as it is too time-consuming. Two promising new tools have emerged - the CRASH and CARG scores - to assign patients to varying intensities of chemotherapy based on a pre-therapy risk assessment. The strengths and shortcomings of each tool were discussed by a group of six advisors with expertise in the treatment of NSCLC. Based on a literature review and on their personal experience, CRASH and CARG were considered feasible toxicity prediction tools, appropriate for implementation in routine clinical practice, with a potentially high impact in optimizing therapy selection for elderly patients with cancer.

Programa de educación en neurociencias y dolor para pacientes con dolor neuropático crónico: estudio piloto / Multidisciplinary education program in neuroscience and pain for neuropathic pain patients: pilot study

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Comparison between the optical properties of aerosols in the fine and coarse fractions over Valladolid, Spain.

Continuous measurements of the optical properties of aerosol particles have been made at Valladolid, Spain, covering the period from June 2011 to July 2012. The measurements were made at two size cuts: sub-10 µm and sub-1 µm (PM10 and PM1). The data measured were the scattering and backscattering coefficients, σs and σbs, obtained from an integrating nephelometer, and the absorption coefficient, σa, obtained from a particle soot absorption photometer. Spectrally resolved data were obtained from both instruments at 3 wavelengths (blue/green/red) at low relative humidity (RH < 40%). The statistical data for the instruments were calculated based on the hourly averages. For the PM10 fraction, the hourly mean values of σs and σa at 550 nm were 33 Mm-1 (StD = 30 Mm-1) and 4 Mm-1 (StD = 3 Mm-1), respectively. For the PM1 fraction, σs and σa mean values were 16 Mm-1 (StD = 14 Mm-1) and 4 Mm-1 (StD = 3 Mm-1), also at 550 nm. The derived parameters analyzed were the single scattering albedo, ω0, the backscatter fraction, σbs/σs, and the Ångström exponents of scattering, absorption and single scattering albedo, αs, αa and αω0. The contribution of the PM10 and the PM1 fractions for all these parameters plays a central role throughout the paper, allowing an improved classification of aerosol types. Our data are dominated by elemental carbon (EC) and elemental carbon/organic carbon mixed (EC/OC). For the PM10 data, dust dominated aerosol is also observed. Although we found that fine particles contribute more than coarse particles for decreasing the ω0 values, results suggest that it is also necessary to quantify the effect of coarse particles. Fine particles were found to produce ω0 spectra that decrease with the wavelength, αω0 > 0, while PM10 fractions were found to produce spectra that can decrease or increase with the wavelength, 0 < αω0 < 0. Both daily cycle and monthly variations are analyzed and related to local features as well as the transport of particles from elsewhere. A diurnal pattern characteristic of urban areas is observed, but it is less evident on weekends. The main long range transport influences are Atlantic advection, anthropogenic events from Central Europe and dust events.

Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene.

PURPOSE: There is still a considerable percentage of hereditary breast and ovarian cancer (HBOC) cases not explained by BRCA1 and BRCA2 genes. In this report, next-generation sequencing (NGS) techniques were applied to identify novel variants and/or genes involved in HBOC susceptibility. METHODS: Using whole exome sequencing, we identified a novel germline mutation in the moderate-risk gene ATM (c.5441delT; p.Leu1814Trpfs*14) in a family negative for mutations in BRCA1/2 (BRCAX). A case-control association study was performed to establish its prevalence in Spanish population, in a series of 1477 BRCAX families and 589 controls further screened, and NGS panels were used for ATM mutational screening in a cohort of 392 HBOC Spanish BRCAX families and 350 patients affected with diseases not related to breast cancer. RESULTS: Although the interrogated mutation was not prevalent in case-control association study, a comprehensive mutational analysis of the ATM gene revealed 1.78% prevalence of mutations in the ATM gene in HBOC and 1.94% in breast cancer-only BRCAX families in Spanish population, where data about ATM mutations were very limited. CONCLUSION: ATM mutation prevalence in Spanish population highlights the importance of considering ATM pathogenic variants linked to breast cancer susceptibility.